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Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease.


ABSTRACT: Cardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-γ and mitochondrial dysfunction are known to play a major pathogenetic role. Chagas disease provides a unique model to probe for genetic variants involved in inflammatory cardiomyopathy.

Methods

We used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease. We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY.

Results

We identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related - most of the latter involved in proinflammatory cytokine production. Significantly, incubation with IFN-γ on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (ΔψM), indicating mitochondrial dysfunction.

Conclusion

Mitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants. We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-γ-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies.

SUBMITTER: Ouarhache M 

PROVIDER: S-EPMC8249271 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease.

Ouarhache Maryem M   Marquet Sandrine S   Frade Amanda Farage AF   Ferreira Ariela Mota AM   Ianni Barbara B   Almeida Rafael Ribeiro RR   Nunes Joao Paulo Silva JPS   Ferreira Ludmila Rodrigues Pinto LRP   Rigaud Vagner Oliveira-Carvalho VO   Cândido Darlan D   Mady Charles C   Zaniratto Ricardo Costa Fernandes RCF   Buck Paula P   Torres Magali M   Gallardo Frederic F   Andrieux Pauline P   Bydlowsky Sergio S   Levy Debora D   Abel Laurent L   Cardoso Clareci Silva CS   Santos-Junior Omar Ribeiro OR   Oliveira Lea Campos LC   Oliveira Claudia Di Lorenzo CDL   Nunes Maria Do Carmo MDC   Cobat Aurelie A   Kalil Jorge J   Ribeiro Antonio Luiz AL   Sabino Ester Cerdeira EC   Cunha-Neto Edecio E   Chevillard Christophe C  

Journal of clinical immunology 20210303 5


Cardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-γ and mitochondrial dysfunction are k  ...[more]

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